Influenza A viruses are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have results in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe were also of major public health importance. Understanding the molecular basis for the formation of pandemic influenza strains in critical. The 1957 and 1968 pandemics were human-avian reassortant viruses in which two or three influenza gene segments from the then circulating human influenza viruses were replaced with genes from an avian source. Sequence and phylogenetic analysis of the 1918 pandemic virus suggested that it was derived from an avian-like virus in toto. The 1918 pandemic virus caused several epidemiologically distinct waves. The so-called first wave, in the spring and summer months of 1918, may have represented an early form of the virulent second wave.[unreadable] To understand how this pandemic virus emerged and to model its virulence, it is important to place this virus in the context of human influenza viruses circulating before 1918 and to follow the early evolution of human H1N1 viruses after 1918. Because no human influenza isolates are available earlier than 1933, the only way to characterize these viruses is by identification of influenza RNA fragments preserved in formalin-fixed, paraffin-embedded autopsy tissues. With our collaborator, Professor John S. Oxford, post-mortem records of fatal pneumonia cases from 1908-1928 were screened to identify putative influenza cases based on clinical history and post-mortem pathology findings. Promising cases were sectioned for subsequent molecular screening. Sections of post-mortem lung tissues are currently being examined for the presence of influenza A virus RNA fragments by RT-PCR methods previously used to characterize the 1918 pandemic virus from similar samples. [unreadable] [unreadable] Pre-1918 human influenza A viruses:[unreadable] Post-mortem records of fatal pneumonia cases from 1908-1917 were screened to identify putative influenza cases based on clinical history and post-mortem pathology findings. Promising cases were sectioned for molecular screening. A total of 145 such cases are being evaluated for the presence of influenza A virus RNA by RT-PCR with degenerate primers from a conserved region of the matrix gene segment. Several influenza A virus RNA-positive cases have been identified, with RT-PCR templates up to a maximum size of approximately 100 bases. [unreadable] [unreadable] Potential 1918 first wave influenza A viruses:[unreadable] Post-mortem records of fatal pneumonia cases from January-July 1918 were screened to identify putative influenza cases that may reflect first wave cases based on clinical history and post-mortem pathology findings. Promising cases were sectioned for molecular screening. A total of 5 such cases are being evaluated for the presence of influenza A virus RNA by RT-PCR with degenerate primers from a conserved region of the matrix gene segment. [unreadable] [unreadable] Post-1918 human influenza A viruses:[unreadable] Post-mortem records of fatal pneumonia cases from 1919-1928 were screened to identify putative influenza cases based on clinical history and post-mortem pathology findings. Promising cases were sectioned for molecular screening. A total of 200 such cases are being evaluated for the presence of influenza A virus RNA by RT-PCR with degenerate primers from a conserved region of the matrix gene segment. Several influenza A virus RNA-positive cases have been identified, with RT-PCR templates up to a maximum size of approximately 100 bases.